Principal Investigator George H De Vries Title Promotion of Functional Recovery From Demyelinating Disease KeyWords Exp. Autoimmune Enceph. MS, Demyelinating Diseases, Inflammation. Purpose- Functional loss after demyelination is a one of the major problems of veterans seeking treatment at VA medical centers. It is estimated that currently there are 20,000 veterans who are actively receiving treatment for multiple sclerosis (MS) which is the major demyelinating disease affecting young adults. Often MS begins as a series of exacerbations and remissions which eventually over a period of years resolves into a progressive course with no remissions. Current FDA treatments are focused on decreasing the number and frequency of exacerbations. Our hypothesis is: Functional recovery from chronic demyelination can be achieved by recruiting intact neurons in the CNS to sprout and restore function to the lost pathways (neuroplasticity). In order to test this hypothesis we will develop a model of chronic focal demyelination (targeted EAE-tEAE) developed in our laboratory which results in the functional loss of a behavioral task in our case a skilled forelimb retrieval task. Plasticity will be evaluated by labeling the contralateral intact pathway and determining the degree to which the labeled fibers attempt to sprout and take over lost function by crossing the midline. This measure of plasticity has been successfully used in the stroke model by our collaborator Dr. G. Kartje. Functional recovery will be evaluated as a measure of neuroplasticity. There are three two objectives for the proposed research: 1. To develop and characterize a t-EAE model in which there is a persistent immune-mediated lesion. 2.To evaluate the ability of the rat rehabilitation plus enriched enviorment to promote recovery after t-EAE It is anticipated that the results of this study will form the basis for the use and evaluation of the other strategies to enhance neuroplasticity which combined with rehabilitation will quickly and effectively promote functional recovery. PUBLIC HEALTH RELEVANCE: Relevance of Proposed Work to the VA Patient Care Mission Developing more effective rehabilitation strategies to promote functional recovery of veterans affected by demyelinating disease is the goal of this research proposal which is highly relevant to the VA patient care mission. Improved rehabilitation strategies with improved functional recovery outcome will certainly improve the quality of life for veterans afflicted with demyelinating disease such as multiple sclerosis. The VA has been estimated to provide care to 20,000 patients with MS each year. There is a double benefit to improved quality of life since it will not only impact the functional ability of the individual with MS, but functional recovery will also reduce the caregiver burden and may lead to a reduction in long-term treatment costs. The cost of providing medical and nursing care to an individual with MS has been estimated at over 34,000 dollars per year, with a per individual lifetime cost of 2.2 million (Whetten-Goldstein, Sloan, Goldstein, &Kulas, 1998). It should be noted that this estimate does not include intangible costs such as increased caregiver burden, and decreased quality of life - costs that may be associated with impairment in functional ability. The results of the proposed investigation will be directly transferrable to rehabilitation strategies since the results will provide a proof of principle that rehabilitation can increase plasticity and in this way promote functional recovery.